The long term objective of the applicant is a better understanding of the role of genetic and environmental factors in human neuropsychiatric disorders through the study of the specific disorder, Gilles de la Tourette's syndrome (TS). Recent research has led to several notable advances in our understanding of TS: 1) there is a greater range of phenotypic expression than was thought (including obsessive compulsive disorder (OCD));.2) TS and related conditions are much more common than had previously been considered; and 3) the disorder appears to be transmitted As an autosomal dominant trait. Furthermore, its prevalence and its debilitating effect on those afflicted makes the syndrome a major public health problem. Understanding the genetics of TS will be of direct benefit to patients concerned about recurrence in their families; ultimately, clarifying the genetics of TS may elucidate its pathogenesis. Data collection has been completed for 102 TS and control families. Results from preliminary analyses of these data replicated our earlier findings which suggested that there is an etiologic relationship between TS and OCD and that the mode of transmission of-TS and related-disorders is consistent with autosomal dominant inheritance. In this application we propose to study another 100 families of OCD and control probands so that it will be possible to characterize more completely the nature of the relationship between TS and OCD. Tn addition, data collection for a genetic linkage study in 5 large multigenerational families of TS probands will be continued. The linkage data will allow us to confirm our findings from segregation analyses and to isolate and characterize any genetic locus. Finally, a prospective study of young unaffected children at risk for TS will be expanded. Forty children and their parents have already been enrolled in the study. We plan to increase our sample size to 50. This study will help to identify "non-genetic" factors important for onset and manifestation of the disorder, Data from these new subject samples will help identify specific genetic and environmental factors associated with the variable expression of TS and related behaviors. The proposed award will enable the applicant to continue to focus on the study developmental psychopathology. The professional growth projected will allow continued integration of family study design, prospective risk research, metabolic assessment and-linkage studies using RFLPS. This combination should provide powerful methods for the continuing study of childhood behavioral disorders.